PROJECT SUMMARY Comorbid expression of alcoholism and depression is extremely common. Thus, it is critical to determine how the neurobiological components of these conditions overlap to advance our understanding of the common risk factors and mechanisms that influence this comorbidity. The information derived from these investigations helps to contribute to the development of therapeutics that can be used to target specific populations of alcoholic patients. Recently, our group has described a bidirectional relationship between alcohol exposure and depression-like behavior using the social defeat stress (SDS) paradigm, a major preclinical model of depression. In this model, male mice are physically defeated by a larger conspecific and then housed on the other side of a transparent divider. When exposed chronically to this stressor, mice will exhibit behavioral phenotypes that are thought to be indicative of depressive-like behavior, including anhedonia and social withdrawal. One drawback of the SDS model is that it only works effectively in male subjects due to sex differences in aggressive behavior in mice. The objective of the current proposal is to establish a model in our laboratory that will allow us to assess the relationship between alcohol seeking and depressive-like behavior in both female and male subjects. To achieve this objective, we will utilize a recently developed model where a test subject observes the social defeat of another animal, called vicarious defeat stress (VDS). VDS involves observation of social defeat sessions from a compartment neighboring where the defeat is taking place. It was recently published that this model produces similar depressive-like phenotypes in both male and female mice. In the proposed studies, we will use the VDS protocol to investigate the relationship between depression-like behavior and alcohol consumption in male and female mice. Furthermore, we will determine if chronic alcohol administration alters the sensitivity to subsequent VDS exposure. These studies will advance our current knowledge of the mechanisms underlying comorbid depression and alcoholism in both males and females. The results obtained from this proposal will provide an experimental foundation that can be used for future projects assessing the mechanisms underlying these processes and for the identification of promising therapeutic targets.